Obesity is a major cause for the development of debilitating diseases such as type-2 diabetes, cardiovascular disease, hypertension, renal diseases, non-alcoholic steatohepatitis (NASH), all of which reduce life quality as well as lifespan. Despite enormous efforts to develop anti-obesity medications, the drugs that are currently available have had only marginal effects (in the range of 3?10%) on body weight, and most have been withdrawn from the market owing to their side effects. Therefore, there is an urgent need for safe and effective medical treatments for obesity Leptin, an adipose tissue-derived hormone that communicates the status of peripheral energy reserves to the brain has robust influence on appetite suppression and on increasing energy expenditure. These features of leptin initially created great excitement for the treatment of obesity; however the development of leptin resistance in the brains of obese individuals has prevented its use as an effective anti-obesity therapeutic. We and others have previously shown that increased Endoplasmic Reticulum (ER) stress in leptin- responsive neurons in the brain plays a central role in the development of leptin resistance, and consequently of obesity. To translate our molecular biology discoveries into treatment, we used systems biology approaches and unconventional in-silico drug screens powered with mathematical algorithms, to target ER stress. We have discovered Celastrol and Withaferin A as powerful chemical chaperones that alleviate ER stress, restore insulin and leptin sensitivity, and reduce the bodyweight of obese mice to lean levels. The effect of Celastrol on bodyweight (~45-50% reduction) is stronger than that which follows bariatric surgery. We have subsequently focused on the molecular mechanisms of action of Celastrol in increasing leptin sensitivity. These efforts revealed interleukin 1 receptor 1 (IL1R1) as an intermediate mediator of Celastrol's action: we have shown that IL1R1 KO mice are completely resistant to Celastrol's leptin sensitizing and anti- obesity effect. Our proposal is based on these previous observations and has three Specific Aims. Aim 1 and Aim 2 focus on identification of hypothalamic neuron populations that mediate Celastrol's anti-obesity and anti- diabetic effects. Furthermore, these aims plan to determine the contribution of each identified neuron population to the different aspects of Celastrol's anti-obesity and anti-diabetic effects. Aim3 proposes to determine the molecular mechanisms of Celastrol action and utilizes state-of-art techniques to identify molecular networks affected by Celastrol. The ultimate goal of this aim is to determine the exact target of Celastrol in mediating leptin sensitization and consequently its anti-obesity and anti-diabetic effects.